The predominant route of HIV transmission occurs across mucosal tissues. The earliest events that occur at the sites of transmission are poorly understood, yet an understanding of these events may provide critically important information that can be utilized in the development of an effective HIV vaccine. Multiple lines of investigation reveal that transmission of HIV across mucosal surfaces is inefficient. The virus must overcome multiple structural barriers and ultimately infect metabolically active CD4+ T cells. The process of infection requires that the HIV envelope protein first binds to the CD4 receptor and subsequently to a co-receptor, either CCR5 or CXCR4. However, the CD4 receptor is expressed at high levels not just on metabolically activated cells, but also on resting cells, which are a poor substrate for productive infection. We have identified the integrin alpha4-beta7 as an additional HIV receptor on the surface of CD4+ T cells. Unlike the CD4 receptor, integrin alpha4-beta7 is expressed on a subset of cells in mucosal tissues that tend to be metabolically activated. We hypothesize that the direct interaction between HIV gp120 and alpha4-beta7 provides two advantages to HIV that allow it to transmit across mucosal surfaces in a more efficient manner. By engaging alpha4-beta7 on a susceptible cell, a virion is able to target an important subset of CD4+ T cells that is highly susceptible to infection. In addition, alpha4-beta7+ CD4+ T cells migrate from genital mucosa into gut lymphoid tissues where an optimal cellular environment exists for viral replication. In this way, the specific affinity of the HIV envelope for alpha4-beta7 provides a plausible mechanistic explanation for the preferential establishment and/or maintenance of HIV replication in GALT. Understanding the specific molecular events surrounding mucosal transmission will hopefully allow us to identify new strategies to prevent HIV transmission.